Identifying Therapeutic Targets of Accelerated Sarcopenia

The proposed research is designed to identify the mechanisms that can accelerate loss of muscle size, strength and physical function in type 2 diabetes and with hospitalization in older persons. About ⅓ of older Americans have type 2 diabetes, and about ⅓ of the hospitalizations in the USA involve persons older than 65 year of age. The proposed research is relevant to the part of NIH's mission that pertains to development of the fundamental knowledge that will improve health and reduce the burdens of disability, because this work will provide the fundamental evidence to identify new targets for the development of innovative treatments to slow down muscle loss and disability in our aging society.

Sarcopenia is a major contributor to frailty and increases the risk of falls, physical dependence, disability and mortality in older adults. It advances slowly with healthy aging. However, diseases or other insults and injuries can accelerate sarcopenia and lead to catastrophic declines in mobility and independence. For example, chronic diseases such as Type 2 Diabetes Mellitus (T2DM) are associated with accelerated loss of muscle mass and function in seniors; hospitalization with bed rest inactivity acutely accelerates sarcopenia. What it is not know is how concurrent diseases, inactivity or other insults and injuries accelerate sarcopenia in older adults. This knowledge gap hinders the development of innovative, targeted treatments for this disabling condition. The objective of this research is to examine the basic mechanisms that underlie accelerated sarcopenia in older adults and identify potential targets for interventions. The central hypothesis is that a global and fundamental mechanism of acute or chronic acceleration of sarcopenia is a reduction in skeletal muscle amino acid transport, which decreases muscle protein anabolism, and can be reversed by activation of the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling with a non-amino acid stimulus, such as exercise. Amino acid transport is an active process that controls intracellular amino acid availability and the activation of protein synthesis in skeletal muscle. It is regulated by amino acid concentrations and non-amino acid stimuli that activate mTORC1 signaling, such as resistance exercise and insulin.The central hypothesis will be tested with the following specific aims: 1) Determine the effect of T2DM on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 2) Determine the effect of short-term bed rest inactivity on the sensitivity of skeletal muscle amino acid transport to dietary amino acids. 3) Determine the effect of resistance exercise on the sensitivity of amino acid transport to dietary amino acids in acute and chronic accelerated sarcopenia induced by inactivity or T2DM. Amino acid transport and protein metabolism in muscle will be measured using integrative molecular, imaging and stable isotope methodologies, identifying specific upstream regulators involved in the anabolic resistance of accelerated sarcopenia that can be targeted with novel treatments to reduce sarcopenia and improve independence in older adults.

Type 2 diabetes subjects will undergo 3 months of resistance exercise training. Muscle size, strength and response to a low dose amino acids will be measured before and after training. Results of this arm will be compared to those previously obtained in healthy older subjects who participated in NCT02999802 (same training protocol) after 1:1 matching for age and sex.

Healthy subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.

Healthy subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a high dose amino acids (HAA) will be measured before and after bed rest.

Type 2 diabetes (T2DM) subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.

Type 2 diabetes (T2DM) subjects will undergo short term bed rest with standard of care physical therapy. Muscle size, strength and response to a high dose amino acids (HAA) will be measured before and after bed rest.

Healthy subjects will undergo short term bed rest with intensive physical therapy (PT). Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.

Type 2 diabetes (T2DM) subjects will undergo short term bed rest with intensive physical therapy (PT). Muscle size, strength and response to a low dose amino acids (LAA) will be measured before and after bed rest.

Inclusion Criteria: Body mass index: <40 kg/sq meter Score ≥26 on the 30-item Mini Mental State Examination Stable body weight for at least 3 months Non-diabetic or with Type 2 Diabetes Mellitus Exclusion Criteria: Pre-diabetes per American Diabetes Association criteria Insulin therapy, significant diabetic complications, or A1c>8% Impairment in Activities of Daily Living >2 falls/year weight loss >5% in the past 6 months Exercise training (≥2 sessions/week) or ≥10,000 steps/day Significant cardiovascular, liver, renal, blood, or respiratory disease Active cancer or infection Recent (within 3 months) treatment with anabolic steroids, systemic corticosteroids or estrogen. Alcohol or drug abuse